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            <Paragraph Margin="0,20,0,0" FontSize="13pt"  FontWeight="bold">Nephrol Dial Transplant (1997) 12: 776–780</Paragraph>


            <Paragraph Margin="10,20" LineHeight="16pt">
                <Italic FontSize="14pt" >Case Report</Italic>
            </Paragraph>

            <Paragraph  FontSize="11pt" Margin="10,20" LineHeight="16pt">
                <Bold>Alport syndrome and diffuse leiomyomatosis with major morbid events presenting at adult age</Bold>
            </Paragraph>



            <Paragraph Margin="10">
                <Bold>Key words:</Bold> Alport syndrome; cataract; COL4A5 gene; COL4A6 gene; oesophageal leiomyoma; leiomyomatosis<LineBreak/>
            </Paragraph>

            <Paragraph Margin="10,20" LineHeight="18pt" FontSize="14pt" >
                <Bold>Introduction</Bold>
            </Paragraph>

            <Paragraph Margin="10">
                Alport syndrome (AS) is a familial nephropathy characterized by: (1) a history of haematuria with or without chronic renal failure; (2) ultrastructural evidence of irregular thickening
                or thinning of the glomerular basement membrane (GBM), and/or splitting of the lamina densa; (3) progressive bilateral sensorineural
                deafness for high tones and (4) ocular changes, including anterior lenticonus and retinal flecks [1–3].
                According to Flinter et al., at least three of these four characteristics should be present to establish the diagnosis
                of AS in a family [4]. Conditions, such as hyperprolinaemia, hyperaminoaciduria, ichthyosis,
                development of serum antithyroid antibodies, hypoparathyroidism, serum IgA deficiency, granulocyte inclusions,
                or macrothrombocytopenia have been reported in association with AS [1,2].<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                AS with diffuse leiomyomatosis (ASDL) is defined by the association of AS with oesophageal, gastric, vulvovaginal,
                and bronchial leiomyomas, and clitoral hypertrophy [5].<LineBreak/>
            </Paragraph>

            <Paragraph Margin="10" TextIndent="25">
                ASDL was first recognized as a specific clinical entity by Garcia-Torres and Guarner in 1983 [6]. Since then,
                a number of clinical reports have been published, mainly in the paediatric literature [6–20], which usually
                focus on a particular aspect of the disease, such ophthalmological [14] or radiological changes [17,18]
                or surgical aspects [7,8,13 ]. Little attention in medical literature concerning adult patients has been
                paid to the clinical history of ASDL [7,14,16 ]. As consequence, ASDL may remain unnoticed when
                patients present with this syndrome at a more advanced age. However, a timely diagnosis is important, in view
                of the morbidity and the inheritance characteristics of the disease.<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                In this paper we report a family with at least four members affected by ASDL and with clinical manifestations
                presenting mainly during adulthood. The variable clinical expression—even within the same family—is illustrated.
                The clinical findings are correlated with the present knowledge on genetic and pathophysiological aspects of ASDL.<LineBreak/>
            </Paragraph>

            <Paragraph Margin="10,20" LineHeight="18pt" FontSize="14pt" >
                <Bold>Case reports</Bold>
            </Paragraph>

            <Paragraph Margin="10">
                Patient 1. (III,5) (the index patient) is a young woman, born in 1974, who at age 16 presented in the department
                of nephrology because of haematuria (>200 RBC/HPF). She developed dysphagia for solid food and nausea without
                vomiting in 1987. Her family history was positive for dysphagia and nephropathy (Figure 1).<LineBreak/>
            </Paragraph>

            <Paragraph Margin="10" TextIndent="25">
                Clinical examination and biochemical analysis of the blood, including renal function tests, were normal.
                Proteinuria was 0.7 g/24 h. The urinary sediment contained 20 RBC/HPF without leukocyturia. Endogenous
                creatinine clearance was 113 ml/min. A chest X-ray suggested a right paracardiac mass. A barium
                swallow study showed narrowing of the distal oesophagus with distension of the upper segment
                ( Figure 2). These radiological findings, together with the results of endoscopy and manometry, were found
                compatible with achalasia. Computerized axial tomography of the chest confirmed the oesophageal dilatation;
                in addition, displacement of the distal lumen from the midline to the right with filiform luminal
                narrowing due to the presence of a tumoural mass with focal zones of wall thickening, was observed
                ( Figure 3). The tumour had a density of solid tissue and was located in the lower third of the oesophagus
                extending into the upper portion of the stomach. Echography of the kidneys and audiometry were
                normal. Ophthalmological investigation revealed congenital cataract and pronounced thickening of both
                lenses. A renal biopsy showed non-specific findings on light-microscope examination. Electron-microscopy
                disclosed irregular thickening of the glomerular basement membrane with splitting of the lamina densa
                (Figure 4A). Immunofluorescence was negative. Based on these data, the diagnosis of Alport syndrome was
                established.<LineBreak/>
            </Paragraph>


            <Paragraph Margin="10" TextIndent="25">
                In July 1991 a thoracotomy was performed for enucleation of a tumour (20×15 cm) in the lower oesophagus, which
                extended over a length of 10 cm in the upper stomach; an antireflux procedure (according to Belsey) was performed.
                Histological studies revealed an irregular pattern of smooth muscular bundles with benign appearance, compatible
                with the diagnosis of leiomyoma ( Figure 4B). After a few months, the patient developed severe complaints of
                pyrosis and dysphagia. Reflux oesophagitis was discovered endoscopically, refractory to ranitidine (150 mg bidaily)
                and to omeprazole (20 mg daily); the patient became only asymptomatic with high doses of omeprazole and
                cisapride. In January 1992, a new antireflux intervention (fundiplication according to Toupet) with supraselective
                vagotomy was performed. Relapse of reflux oesophagitis necessitated again maximal combined pharmacological treatment.
                In May 1993, total oesophagectomy was performed with gastric pull-up (three-field technique). Since then the patient
                has been free of dysphagic complaints.<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                In April 1992 three vulvar leiomyomas were resected. Molecular studies in this patient demonstrated a
                deletion of the 5¾ part of the COL4A5 gene, extending into the COL4A6 gene, with deletion of exons 1 and
                2, the deletion breakpoint being localized in intron 2 of the COL4A6 gene [21].<LineBreak/>
            </Paragraph>

            <Paragraph Margin="10" TextIndent="25">
                Until now, renal function remains normal, although
                haematuria and proteinuria persist.
                Patient 2. (II,3 ), born in 1948, is the mother of the
                index patient. She had complaints of dysphagia with COL4A5 and COL4A6 genes as the lesion found in
                her daughter ( patient 1) [21].
                Besides her daughter, patient 2 has one son, born in
                1972, who is in good health with a normal urinary
                sediment. He has no gastrointestinal, auditory, or
                visual complaints.
                Patient 3. ( II,2), born in 1946, is the uncle of the
                propositus. He developed recurrent bronchitis, dysphagia
                with retrosternal pain and frequent vomiting
                during childhood. He needed a dental prosthesis at the
                age of 4. Proteinuria and haematuria were detected at
                the age of 5. He developed progressive renal failure
                from 1958 and had end-stage renal disease at the age
                of 23 (serum creatinine 18 mg/100 ml). Bilateral cataract
                and bilateral high-tone sensorineural hearing loss
                were observed. The diagnosis of AS was retained based
                on the clinical and biochemical findings. Barium studies
                of the oesophagus revealed marked distension of the
                distal part with delayed transit to the stomach. A renal
                transplantation was performed in March 1970; the
                patient died from fungal peritonitis 3 months later,
                despite adequate graft function.<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                Patient 4. (I,2 ) born in 1923, is the grandmother of
                the propositus. She complained of dysphagia since her
                youth, but never had specific investigations until
                recently, at age 71, when her clinical condition deteriorated.
                A weight loss of more than 15 kg in 12 months,
                due to extreme dysphagia for solid food was observed.
                A barium oesophagogram disclosed a megaoesophagus
                with narrowing of the distal part. The
                patient refused further examinations as well as surgical
                treatment. Serum creatinine has been normal up to
                now; urinary analysis could not be obtained. Her
                parents, four brothers and one sister all lived into their
                seventies without clinical problems that could be
                related to ASDL.<LineBreak/>
            </Paragraph>

            <Paragraph Margin="10,20" FontSize="14pt" >
                <Bold>Discussion</Bold>
            </Paragraph>

            <Paragraph Margin="10" TextIndent="25">
                In this paper we present a family with clinical manifestations
                of ASDL in at least four members in three
                generations (Figure 1).<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                The present family conforms with the diagnostic
                criteria of AS, as proposed by Flinter et al.[4]. More
                severe expression of renal disease was observed in male
                versus female family members, as is currently observed
                in X-linked disorders. In contrast, the symptoms of
                oesophageal leiomyomatosis were as severe in the three
                female patients as in the male patient. This suggests
                that oesophageal involvement is fully expressed in
                females, with complete penetrance, in contrast to mani-
                festations of renal disease, which are in general more
                pronounced in men [22].<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                The mother of the propositus (patient 2) showed no
                proteinuria and only sporadic haematuria. It should
                be remembered that in women with AS, renal involvement
                can be mild or even absent. At least one female
                has been reported who presented with DL but without
                signs of nephropathy, in whom the molecular gene
                defect associated with ASDL was found, thus establishing that this patient was a carrier of AS [22].
                Most of the ASDL patients reported so far needed
                surgical interventions during childhood [6,9,11–13,-
                (15–16,18–20]. In contrast, in the index patient and
                her mother, surgery was performed only at the age of
                17 and 30 years respectively, whereas the grandmother
                lived for more than 70 years without surgery. Also the
                only affected male (patient 3) had no surgical interven-
                tion for his oesophageal problems.<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                The diagnosis of oesophageal leiomyomatosis may
                be delayed or may be mistaken as achalasia, based on
                the clinical presentation and the results of radiographic
                studies, endoscopy, and manometry [5,13,15,18].
                Computerized tomography is more appropriate to
                establish the diagnosis and to evaluate the extension
                of the leiomyomas, especially when they present as
                nodular masses. Diffuse invasion of the oesophageal
                wall by leiomyomatosis may be more difficult to recog-
                nize and the real extent may be underestimated.<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                In view of the important clinical and genetic implica-
                tions, renal function and urinary status should be
                controlled in any patient with oesophageal leiomyom-
                atosis. Conversely, the possibility of ASDL should be
                considered in AS patients with dysphagia.<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                Potentially fatal pulmonary complications have been
                observed in several patients and were attributed to
                tracheobronchial localization of leiomyomas [6].
                Recurrent bronchitis disappeared after oesophageal
                surgery in the mother of our index patient, suggesting
                that the pulmonary problems were due to aspiration
                pneumonia, secondary to the mega-oesophagus.<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                Better insights have recently been obtained in the
                genetics of AS and ASDL. X-linked inheritance is
                present in 85% of patients with classical AS [23]. AS
                is characterized by structural changes in the glomerular
                basement membrane, of which collagen type IV is the
                major component. Type IV collagen are molecules with
                a triple helical structure containing three polypeptides
                or a-chains. Six different a-chains, which differ considerably
                with respect to tissue distribution, have already
                been identified [24]. The a5(IV ) and a6(IV ) chains
                are encoded by the COL4A5 and COL4A6 genes,
                located in the Xq.22 region in a head to head configuration
                [21]. A range of deletions, point mutations
                and gene rearrangements in the COL4A5 gene have
                been identified in AS patients [25–27]. Mutations
                involving only the COL4A6 gene have not yet been
                reported.<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                Antignac<Italic>et al.</Italic>  [19] and Zhou <Italic>et al.</Italic> [21] demonstrated
                that ASDL deletions including the 5’ region of
                the COL4A5 gene extended into the COL4A6 gene.
                Heidet et al. [28] reported the consistent presence of a
                deletion breakpoint in the second intron of the
                COL4A6 gene in seven patients with ASDL. The
                molecular studies performed in the present family
                disclosed similar findings. Hence, it has been hypothes-
                ized that mutations of the COL4A6 gene play an
                essential role in the development of leiomyomatosis.
                Recently, however, combined deletions in the COL4A5
                and COL4A6 genes have been demonstrated in some
                patients with classical AS without leiomyomatosis. In
                some, the deletion included an even larger part of the
                COL4A6 gene than was seen in ASDL patients. It has
                therefore been suggested that localization of the
                breakpoint in intron 2 of the COL4A6 gene, as is the
                case in this family, is specifically related to the develop-
                ment of DL. It is thought that localization of the
                deletion breakpoint in intron 2 may trigger the activa-
                tion of a cryptic promotor, resulting in the transcription
                of otherwise non-expressed sequences [28]. This
                mechanism may explain the high penetrance and similar
                phenotypic expression of DL in women and men.
                <LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                Expression studies in fetal tissues of a 24-week-old
                human fetus showed the presence of an a5(IV) mRNA
                in the BM of most tissues, whereas a6(IV ) mRNA
                was found only in meninges, oesophagus, choroid
                plexus, and stomach [21]. This tissue distribution may
                explain the clinical picture of ASDL, with leiomyom-
                atosis of the oesophagus as an almost obligatory
                feature.<LineBreak/>
            </Paragraph>

            <Paragraph Margin="10" TextIndent="25">
                Bilateral congenital or juvenile cataract has been
                observed in a substantial number of patients with
                ASDL [5], although it is rare in classical AS [3,14].
                In contrast to the nephropathy, the cataract may be
                as severe in women as in men. The presence of cataract
                in ASDL is possibly also related to the specific localiz-
                ation of the deletion breakpoint in the COL4A6 gene,
                triggering the activation of a cryptic cataract-causing
                gene.<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                Several members in this pedigree developed severe
                early dental loss. In patient 3, a dental prosthesis was
                already required at the age of 4. As collagen type IV
                is present in the biochemical composition of the periodontal
                ligament [29], which is part of the tooth attach-
                ment apparatus, a structural defect of this collagen
                type may explain the early dental loss.<LineBreak/>
            </Paragraph>
            <Paragraph Margin="10" TextIndent="25">
                In conclusion, diffuse leiomyomatosis associated
                with AS is an X-linked genetic disorder with important
                clinical complications, in children as well as in adults.
                So far, this syndrome comes to attention mainly in the
                paediatric literature. The present report underscores
                the point that the first major morbid events of the
                disease may be delayed until adulthood. Patients with
                AS should be examined for signs of leiomyomatosis
                and vice versa. Genetic studies in this family have shed
                new light on the molecular basis underlying AS and
                DL as well as on tumorigenesis in general.<LineBreak/>
            </Paragraph>
            <Paragraph></Paragraph>
            <Paragraph Margin="10" FontSize="14pt" >
                <Bold>References</Bold>
            </Paragraph>
            <Paragraph></Paragraph>
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            <Paragraph></Paragraph>
            <Paragraph></Paragraph>
            <Paragraph TextIndent="30">
                <Italic>Received for publication: 19.11.96</Italic>
            </Paragraph>
            <Paragraph TextIndent="30">
                <Italic>Accepted for publication: 27.11.96</Italic>
            </Paragraph>
        </FlowDocument>
